DESCRIPTION: In epithelial cells, one of the changes from a normal to a malignant state involves the acquisition of several distinct changes, including a lessening in degree of cell-cell adhesion. The tumor promoter TPA and the cytokine Scatter Factor both disrupt cell-cell junctions. It is possible that TPA is acting on at least part of the signal transduction mechanism regulated by SF/HGF. Preliminary data suggests that PKC alpha and delta isoforms are active in this process. In addition, the mechanism of PKC-mediated disruption of cell junctions does not involve the Map kinase pathway but rather direct modulation of cytoskeletal components via glycogen synthase kinase (GSK3) and the adenomatous polyposis coli gene product (APC). The specific hypothesis of this proposal is that the disruption of cell-cell junctions via the SF/HGF signaling involves PKC acting directly on the GSK/APC pathway and that its upstream activation involves PI3K and ras. The specific aims are 1) identify the proteins affected by PKC and SF/HGF, 2) express a dominant-negative PKCdelta in LLC-PK1 cells, 3) express wild-type and dominant-negative versions of GSK3 and assess GSK3 as a PKC target in cell adhesion disruption, 4) characterize the interaction of ras with PKC in the disruption of cell adhesion, and 5) characterize the role of PI3K as an activator of PKC.